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Tuberculosis (Edinb). 2011 Jul;91(4):277-86. doi: 10.1016/j.tube.2011.03.005. Epub 2011 Apr 11.

Effective inhibitors of the essential kinase PknB and their potential as anti-mycobacterial agents.

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1
Division of Mycobacterial Research, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, United Kingdom. k.lougheed@imperial.ac.uk

Abstract

PknB is an essential serine/threonine kinase of Mycobacterium tuberculosis with possible roles in a number of signalling pathways involved in cell division and metabolism. We screened a library of >50,000 compounds for inhibitors of the in vitro phosphorylation of GarA (Rv1827) by PknB and identified a number of inhibitors. A program of synthetic medicinal chemistry was subsequently conducted around one class of inhibitors and was successful in generating ATP competitive inhibitors with potency in the nanomolar range. Compounds in this class showed cross-reactivity with the related M. tuberculosis kinase, PknF, but not with PknG in an in vitro autophosphorylation assay. These synthesised inhibitors were able to prevent the growth of M. tuberculosis in an Alamar blue assay and in an intracellular model of infection, but only in the micromolar range. We attempted to determine if cell wall permeability was an explanation for the discrepancy between the potent in vitro compared with relatively poor in vivo activity, but found no evidence that the activity of the inhibitors could be improved by weakening the cell wall. Despite a number of drug discovery efforts attempting to develop inhibitors against PknB, it is yet to be reported that any such inhibitors prevent mycobacterial growth at submicromolar concentrations.

PMID:
21482481
PMCID:
PMC3158675
DOI:
10.1016/j.tube.2011.03.005
[Indexed for MEDLINE]
Free PMC Article
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